1. Field of the Invention
The present invention relates to the use of prodrug derivatives of morphine in effecting transdermal delivery of morphine to the systemic circulation of a mammal.
For purposes of this specification, the term "prodrug" denotes a derivative of morphine which, when administered topically to warm-blooded animals, e.g. humans, is converted into the proven drug, i.e. morphine.
The prodrug forms of morphine of this invention are certain derivatives of morphine which possess a desirable high lipophilicity and biphasic solubility in comparison to the parent compound, morphine, and which are cleaved enzymatically to morphine.
2. Description of the Prior Art
It is generally known and an accepted practice to administer morphine to control chronic pain. Morphine plays a prominent role in the control of pain associated with chronic diseases, especially the chronic pain of cancer, and acute pain, especially the acute pain experienced post-operatively. However, such prior art uses of morphine are subject to serious problems. In addition to the obvious problems associated with potential abuse and addiction, the oral and parenteral administration of morphine for pain control frequently involve wide swings in the pharmacodynamics of the drug over each dosing interval. Furthermore, morphine has a short duration of action and is inefficiently and variably absorbed orally due to first-pass metabolism in the intestine and liver.
During recent years much attention has been paid to the development of transdermal delivery systems as a means of mitigating many of the drawbacks associated with the parenteral or oral route of administration. (Sloan K B, Adv. Drug Delivery Rev. (1989), 67-101) A prerequisite for the development of a transdermal delivery system of morphine and other opioids is, however, that the drugs are capable of penetrating the skin at a sufficiently high rate and are not metabolized during the percutaneous absorption. Morphine which remains the analgesic drug of choice for the treatment of severe pain, unfortunately exhibits, a very limited skin permeability which makes it unsuited for transdermal delivery. For instance, the steady-state flux of morphine through human skin in vitro has been reported to be only 6 ng/cm.sup.2 /h when applied in the form of a saturated solution (pH 7.4). (Roy, S. D., and Flynn, G. L., Transdermal delivery of narcotic analgesics: comparative permeabilities of narcotic analgesics through human cadaver skin Pharm. Res. 6 (1989) 825-832). These poor skin-penetration properties of morphine led to the conclusion that morphine is totally unsuited for transdermal delivery. The very poor ability of morphine to permeate into and through the skin can mainly be ascribed to its poor lipophilicity. Thus, the log P value for morphine is only -0.15 where P is the partition coefficient between octanol and aqueous buffer of pH 7.4 (Roy and Flynn 1989). It has now surprisingly been found that transdermal delivery of morphine can be achieved by the prodrug approach proposed in accordance with the present invention.